Venlafaxine (Effexor®) (1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol) is a therapeutic agent whose efficacy is hypothesized to act through inhibition of serotonin reuptake and, potentially, norepinephrine reuptake in neuronal cells. Norepinephrine activity modulation is purported to occur at higher doses of venlafaxine than those required for serotonin activity modulation. Venlafaxine also has the potential to modulate dopamine activity, though the interaction in vitro is weak and the clinical relevance of this interaction is unknown. The drug substance is sold as a 50/50 racemic mixture of R- and S-enantiomers.

Venlafaxine is converted in vivo by oxidative and conjugative degradation to multiple metabolites, at least 48 of which are documented. The major metabolic pathways include phase I metabolism leading to demethylation at the oxygen and/or nitrogen centers and cyclohexyl ring hydroxylation, as well as phase II metabolism including glucuronidation of the hydroxylated metabolites. Because venlafaxine is metabolized by polymorphically-expressed isozymes of cytochrome P450 including CYPs 2C19 and 2D6, and because it can act as an inhibitor of CYP2D6, its application in polypharmacy is necessarily complex and has potential for adverse events. These CYPs are involved in the metabolism of medications that are typically prescribed concurrently with venlafaxine. This phenomenon increases interpatient variability in response to polypharmacy. An example of the critical need for improvement of venlafaxine is the observed interpatient variability in “poor metabolizers” having either defective CYP2D6 alleles or total lack of CYP2D6 expression. These patients fail to convert venlafaxine to its equipotent metabolite, 0-desmethylvenlafaxine. Venlafaxine also suffers from a short half-life relative to the majority of serotonin reuptake inhibitors. The half-life of venlafaxine in humans is ˜5 hours, while its active metabolite has a T1/2 of ˜11 hours. As a consequence of its 5-11 hour pharmacological half-life, those taking venlafaxine are at significant risk of SRI discontinuation symptoms if the drug is abruptly discontinued. Furthermore, in order to overcome its short half-life, the drug must be taken 2 (BID) or 3 (TID) times a day. An extended release formulation of Venlafaxine is also available; however, it does not significantly increase the carryover of drug to the next day. Most other serotonin reuptake inhibitors (SRIs) have half-lives≥24 hours. The half-life of the primary active metabolite, 0-desmethylvenlafaxine (“ODV”), is longer than that of the parent compound; however, it is still desirable and beneficial to increase the half-life of ODV.
